The present invention relates to a novel cycloalkene derivative which has an inducible nitric oxide (NO) synthetase-derived nitric oxide production-inhibiting effect and/or an inhibitory effect on the production of inflammatory cytokines such as TNF-xcex1, IL-1, IL-6 and the like, and which is useful as a prophylactic and therapeutic agent against diseases including cardiac diseases, autoimmune diseases, inflammatory diseases, central nervous system diseases, infectious diseases, sepsis, septic shock and the like, a method for producing the same and a use of the same.
Nitric oxide (NO) is known to have various important in vivo activities in mammals such as a vasodilating factor in the vascular system [Pharmacol. Rev. Vol. 43, p. 109-142 (1991)], a tumoricidal and bactericidal effect in the immune system [Curr. Opin. Immunol., Vol. 3, p. 65-70 (1991)], and a neurotransmitter in the nervous system [Neuron, Vol. 8, p. 3-11 (1992)]. NO is produced principally from L-arginine by NO synthetase (NOS) and currently is known to exist as three inducible isoforms, namely, neuronal NOS, endothelial NOS and an inducible NOS (iNOS) [Cell, Vol. 70, p. 705-707 (1992)], and the former two are referred to also as constitutive NOS (cNOS) in view of their mode of existence, which is in contrast with the latter iNOS.
cNOS occurs in the vascular endothelial cells and neurons, and is calcium calmodulin dependent and activated by various receptor stimulations to produce a small amount of NO, whereby being considered to contribute to the physiological regulatory effects described above. On the other hand, iNOS is induced in macrophages and a neutrophile by various cytokines and bacterial lipopolysaccharides (LPS) to produce a large amount of NO continuously, which makes it to be believed to have not only the pharmacological effects described above but also cell- and tissue-damaging effects at the site of the production [Immunol. Today, Vol.13, p.157-160 (1992)]. Cells known to express iNOS other than those described above may, for example, be hepatocytes, Kupffer cells, glia cells, vascular smooth muscle cells, vascular endothelial cells, myoendocardium, myocardial cells, mesangial cells, chondrocytes, synovial cells, pancreatic xcex2 cells, osteoclasts and the like [FASEB J., Vol.6, p.3051-3064 (1992), Arch. Surg., Vol.128, p.396-401 (1993), J. Biol. Chem., Vol.44, p.27580-27588 (1994), J. Cell. Biochem., Vol.57, p.399-408(1995)], and NO produced in these cells and tissues is known to be involved in various diseases and pathologies. Accordingly, a substance which inhibits the NO production by iNOS inducible cells is considered to be effective as a prophylactic and therapeutic agent against various diseases such as arteriosclerosis, myocarditis, cardiomyopathy, cerebral ischemic failure, Alzheimer""s disease, multiple sclerosis, septic shock, chronic rheumatoid arthritis, osteoarthritis, gastric ulcer, duodenal ulcer, ulcerative colitis, diabetes, glomerular nephritis, osteoporosis, pneumonia, hepatitis, psoriasis, graft rejection and pain. From this point of view, several iNOS-inhibiting compounds such as L-arginine analogue [Pharmacol. Rev. Vol.43, p.109-142 (1991)], aminoguanidine [Br. J. Pharmacol., Vol.110, p.963-968 (1993)] and S-ethylisothiourea [J.Biol.Chem., Vol.43, 26669-26676 (1994)] have been reported so far. However, each of these compounds is not satisfactory in terms of it""s activity, and has a problematically undesirable inhibitory effect not only on iNOS but also on cNOS which is physiologically active.
On the other hand, cytokines such as TNF-xcex1, IL-1 and IL-6 are secreted from various cells such as monocyte, macrophage, lymphocyte, neutrophile, fibroblast and vascular endothelial cells, and involved widely in inflammation-related biological defense and immune mechanisms [The Cytokine Handbook, 2nd ed., Academic Press Limited (1994), Advances Immunol., Vol.62, p.257-304 (1996)], and thus are referred to as inflammatory cytokines. Since the cells targeted by these cytokines range widely over the inflammatory system, vascular system, central nervous system, hematopoietic system and endocrine system, their biological activities are considered to be diverse, including representative biological activities of TNF-xcex1 and IL-1 which were reported to be (1) a pyrogenic activity, (2) an activation and chemotaxis promotion of inflammatory cells such as macrophage and neutrophile, (3) an induction of inflammatory cytokines and acute phase proteins including IL-1, IL-6, IL-8, TNF-xcex1 and CSF and (4) an enhancement of the production of various chemical mediators such as NO, O2xe2x88x92, PAF, prostaglandin, leukotriene and protease as well as those of IL-6 which were reported to be (1) an induction of acute phase proteins, (2) a thrombocyte-increasing activity, (3) a differentiation and an activation of lymphocytes and NK cells and (4) a osteoclast-increasing activity. However, these cytokines, once produced excessively or produced in a wrong site or at a wrong time, exhibit undesirable biological effects, and are proven to be involved in various diseases such as cachexia due to protozoa, bacteria, fungi, viruses and cancers, allergic diseases, chronic rheumatoid arthritis, abscess, graft rejection, anemia, arteriosclerosis, autoimmune disease, diabetes, central nervous system diseases, inflammatory bowel diseases, cardiac failure, hepatitis, hepatocirrhosis, nephritis, osteoporosis, psoriasis, septic shock and the like. From this point of view, substances which have inhibitory effects or antagonistic effects on the production of TNF-xcex1, IL-1 and IL-6 and the like [Eur. J. Immunol., Vol.18, p.951-956 (1991), Immunol., Vol.83, p.262-267 (1994), Proc. Natl. Acad. Sci., Vol.93, p.3967-3971 (1997), J. Immunol., Vol.147, p.1530-1536 (1991), Immunol. Today, Vol.12, p.404-410 (1991)] were reported to be expected to serve as the therapeutic agents against diseases listed above.
While several therapeutic agents for treating cardiac failure, autoimmune diseases, inflammatory diseases and septic shock have been known, each of them was not excellent in pharmaceutical properties such as efficacy and safety, and thus an objective of the invention is to provide a prophylactic and therapeutic agent against cardiac failure, autoimmune diseases, inflammatory diseases and septic shock which is further improved with regard to the pharmaceutical properties mentioned above.
In view of such circumstances, we made an effort to obtain a prophylactic and therapeutic agent against the diseases listed above which has an inhibitory effect on the NO production and/or the inflammatory cytokine production by an iNOS-inducible cell, and finally have succeeded to synthesize a novel compound represented by the formula: 
wherein R represents an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula: OR1 (wherein R1 represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents) or a group represented by the formula: 
(wherein R1b represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, R1c is, same with or different from R1b, a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, ring A is a cycloalkene substituted by 1 to 4 substituents selected from (i) an aliphatic hydrocarbon group optionally having substituents, (ii) an aromatic hydrocarbon group optionally having substituents, (iii) a group represented by the formula: OR1 (wherein R1 represents the same meaning as mentioned above) and (iv) a halogen atom, R0 represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R0 represent a bond with each other, Ar represents an aromatic hydrocarbon group optionally having substituents, a group represented by the formula: 
represents a group represented by the formula: 
and n is an integer of 1 to 4, or a salt thereof, and a novel compound represented by the formula: 
wherein R represents an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula: OR1 (wherein R1 represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents) or a group represented by the formula: 
(wherein R1b represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, R1c is, same with or different from R1b, a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents), R0 represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R0 represent a bond with each other, Ar represents an aromatic hydrocarbon group optionally having substituents, a group represented by the formula: 
represents a group represented by the formula: 
and n is an integer of 1 to 4, provided that when n is 1 or 2, and (i) R1 is a hydrogen atom or an ethyl group, R0 is a methyl group and Ar is a phenyl group, or (ii) R and R0 represent a bond with each other and Ar is a phenyl group, a 2-methylphenyl group, a 4-bromophenyl group, a 4-methoxyphenyl group or a 2,6-dimethylphenyl group, a group represented by the formula: 
is a group represented by the formula: 
or a salt thereof, which is characterized by a cycloalkene structure having a carboxylate group or a carbonyl group and a sulfonamide group (preferred examples among them include a novel compound represented by the formula: 
wherein R2 represents a hydrogen atom or an aliphatic hydrocarbon group, R1, Ar represent the same meanings as defined above, a group represented by the formula: 
represents a group represented by the formula: 
provided that when Ar is a phenyl group, R1 is an ethyl group and R2 is a methyl group, the group represented by the formula: 
is a group represented by the formula: 
etc.).
Furthermore, the inventors have found that a compound represented by the formula: 
wherein Ra represents an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula: OR1a (wherein R1a represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents) or a group represented by the formula: 
wherein R1a represents the same meaning as defined above, R1b is, same with or different from R1a, a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, R0a represents a hydrogen atom or an aliphatic hydrocarbon group, or Ra and R0a represent a bond with each other, Ara represents an aromatic hydrocarbon group optionally having substituents, a group represented by the formula: 
represents a group represented by the formula: 
n represents an integer of 1 to 4, or a salt thereof which contains (i) the novel compound represented by the formula (Iaa) or a salt thereof, and (ii) the novel compound represented by the formula (Ia) (preferred examples among them include a compound represented by the formula: 
wherein R2a represents a hydrogen atom or an aliphatic hydrocarbon group, R1a and Ara represent the same meanings as defined above, the group represented by the formula: 
represents a group represented by the formula: 
which includes the novel compound (Id) or a salt thereof, etc.) unexpectedly has an excellent NO and/or cytokine production-inhibiting effect and has excellent pharmaceutical properties essential for a prophylactic and therapeutic agent against cardiac failure, autoimmune diseases, inflammatory diseases and septic shock.
It is understood that, in the diseases described above, the inflammatory cytokines such as TNF-xcex1, IL-1 and IL-6 and NO are involved as being complicated with each other rather than as being independent of each other whereby further exacerbating the diseases, and thus a compound having excellent effects, such as an inihibitory effect not only on the NO production but also on the inflammatory cytokine production by an iNOS-inducible cell, can be a more effective prophylactic and therapeutic agent than any conventional agent, resulting in a clinical usefulness.
That is, the present invention relates to:
(1) A compound represented by the formula: 
xe2x80x83wherein R represents an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula: OR1 (wherein R1 represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents) or a group represented by the formula: 
xe2x80x83(wherein R1b represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, R1c is, same with or different from R1b, a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents), R0 represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R0 represent a bond with each other, ring A is a cycloalkene substituted by 1 to 4 substituents selected from (i) an aliphatic hydrocarbon group optionally having substituents, (ii) an aromatic hydrocarbon group optionally having substituents, (iii) a group represented by the formula: OR1 (wherein R1 represents the same meaning as mentioned above) and (iv) a halogen atom, Ar represents an aromatic hydrocarbon group optionally having substituents, a group represented by the formula: 
xe2x80x83represents a group represented by the formula: 
xe2x80x83and n is an integer of 1 to 4, or a salt thereof,
(2) A compound represented by the formula: 
xe2x80x83wherein R represents an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula: OR1 (wherein R1 represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents) or a group represented by the formula: 
xe2x80x83wherein R1b represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, R1c is, same with or different from R1b, a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, R0 represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R0 represents a bond with each other, Ar represents an aromatic hydrocarbon group optionally having substituents, a group represented by the formula: 
xe2x80x83represents a group represented by the formula: 
xe2x80x83and n is an integer of 1 to 4, provided that when n is 1 or 2 and (i) R1 is a hydrogen atom or an ethyl group, R0 is a methyl group and Ar is a phenyl group or (ii) R and R0 represent a bond with each other and Ar is a phenyl group, a 2-methylphenyl group, a 4-bromophenyl group, a 4-methoxyphenyl group or a 2,6-dimethylphenyl group, a group represented by the formula: 
xe2x80x83is a group represented by the formula: 
xe2x80x83or a salt thereof,
(3) A compound as defined in (2), wherein the compound represented by the formula (Ia) is a compound represented by the formula: 
xe2x80x83wherein R2 represents a hydrogen atom or an aliphatic hydrocarbon group, R1, Ar, n and the group represented by the formula: 
xe2x80x83represent the same meanings as defined in (2), provided that when n is 1 or 2, Ar is a phenyl group, R1 is a hydrogen atom or an ethyl group and R2 is a methyl group, the group represented by the formula: 
xe2x80x83is a group represented by the formula: 
(4) A compound as defined in (2), wherein the compound represented by the formula (Ia) is a compound represented by the formula: 
xe2x80x83wherein Ar and n represent the same meanings as defined in (2),
(5) A compound as defined in (1), wherein the compound represented by the formula (Iaa) is a compound represented by the formula: 
xe2x80x83wherein each symbol represents the same meaning as defined in (1),
(6) A compound as defined in (5), wherein the ring A is a cycloalkene substituted by lower alkyl, phenyl or halogen, R1 is a lower alkyl group, Ar is a phenyl group optionally having substituents, and n is 2,
(7) A compound as defined in (3), wherein R1 is a lower alkyl group optionally having substituents,
(8) A compound as defined in (3), wherein R1 is an ethyl group,
(9) A compound as defined in (3), wherein R2 is a hydrogen atom or a lower alkyl group,
(10) A compound as defined in (3), wherein R2 is a hydrogen atom,
(11) A compound as defined in (3), wherein Ar is a phenyl group optionally having substituents,
(12) A compound as defined in (3), wherein Ar is a phenyl group substituted by halogen or/and lower alkyl,
(13) A compound as defined in (3), wherein Ar is a group represented by the formula: 
xe2x80x83wherein R4 and R5 are same or different and represents a halogen atom or a lower alkyl group, and n is an integer of 0 to 2,
(14) A compound as defined in (3), wherein the halogen atom is a fluoro atom or a chloro atom,
(15) A compound as defined in (3), wherein the group represented by the formula: 
xe2x80x83is a group represented by the formula: 
xe2x80x83wherein n is the same meaning as defined in (2),
(16) A compound as defined in (3), wherein n is 1 to 3,
(17) A compound as defined in (3), wherein R1 is a lower alkyl group optionally having substituents, R2 is a hydrogen atom or a lower alkyl group, Ar is a phenyl group optionally having substituents, n is 1, 2 or 3,
(18) A compound as defined in (3), wherein R1 is a lower alkyl group optionally having substituents, R2 is a hydrogen atom, Ar is a phenyl group substituted by a halogen atom, n is 2,
(19) A compound as defined in (4), wherein Ar is a phenyl group optionally having substituents, n is 2,
(20) A compound as defined in (2), wherein the compound represented by the formula (Ia) is a compound represented by the formula: 
xe2x80x83wherein R1, R2 and Ar represent the same meanings as defined in (3), a group represented by the formula: 
xe2x80x83represents a group represented by the formula: 
xe2x80x83provided that when Ar is a phenyl group, R1 is a hydrogen atom or an ethyl group and R2 is a methyl group, the group represented by the formula: 
xe2x80x83is a group represented by the formula: 
(21) A compound as defined in (2) which is d-ethyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate or a salt thereof,
(22) A compound as defined in (2) which is ethyl 6-[N-(2,4-chlorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate or a salt thereof,
(23) A compound as defined in (2) which is ethyl 6-[N-(2-chloro-4-methylphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate or a salt thereof,
(24) A compound as defined in (2) which is d-ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate or a salt thereof,
(25) A method for producing a compound as defined in (3) which comprises reacting a compound represented by the formula: 
xe2x80x83wherein R1 and n represent the same meanings as defined in (3) and X1 represents a leaving group, or a salt thereof with a compound represented by the formula: 
xe2x80x83wherein each symbol represents the same meaning as defined in (3), or a salt thereof,
(26) A method for producing a compound as defined in (4) which comprises subjecting a compound represented by the formula: 
xe2x80x83wherein each symbol represents the same meaning as defined in (4), or a salt thereof to a ring-closing reaction,
(27) A method for producing a compound as defined in (20) which comprises reacting a compound represented by the formula: 
xe2x80x83wherein R1 represents the same meanings as defined in (20) and X1 represents a leaving group, or a salt thereof with a compound represented by the formula: 
xe2x80x83wherein each symbol represents the same meaning as defined in (20), or a salt thereof,
(28) A pharmaceutical composition which contains a compound represented by the formula: 
xe2x80x83wherein R represents an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula: OR1 wherein R1 represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents or a group represented by the formula: 
xe2x80x83(wherein R1b represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, R1c is, same with or different from R1b, a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents), R0 represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R0 represents a bond with each other, ring A is a cycloalkene substituted by 1 to 4 substituents selected from (i) an aliphatic hydrocarbon group optionally having substituents, (ii) an aromatic hydrocarbon group optionally having substituents, (iii) a group represented by the formula: OR1 (wherein R1 represents the same meaning as mentioned above) and (iv) a halogen atom, Ar represents an aromatic hydrocarbon group optionally having substituents, a group represented by the formula: 
xe2x80x83represents a group represented by the formula: 
xe2x80x83and n is an integer of 1 to 4, or a salt thereof,
(29) A pharmaceutical composition which contains a compound represented by the formula: 
xe2x80x83wherein Ra represents an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula: OR1a (wherein R1a represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents) or a group represented by the formula: 
xe2x80x83(wherein R1a represents the same meaning as defined above, R1b is, same with or different from R1a, a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, R0a represents a hydrogen atom or an aliphatic hydrocarbon group, or Ra and R0a represent a bond with each other, Ara represents an aromatic hydrocarbon group optionally having substituents, a group represented by the formula: 
xe2x80x83represents a group represented by the formula: 
xe2x80x83n represents an integer of 1 to 4, or a salt thereof,
(30) A pharmaceutical composition which contains a
xe2x80x83compound represented by the formula: 
xe2x80x83wherein R2a represents a hydrogen atom or an aliphatic hydrocarbon group, R1a, Ara, n and the group represented by the formula: 
xe2x80x83represent the same meanings as defined in (29), or a salt thereof,
(31) A pharmaceutical composition which contains a compound represented by the formula: 
xe2x80x83wherein R1a, R2a and Ara represent the same meaning as defined in (30) and the group represented by the formula: 
xe2x80x83is a group represented by the formula: 
(32) The pharmaceutical composition as defined in any one of (28) to (31) which is an agent for inhibiting nitric oxide and/or cytokine production,
(33) The pharmaceutical composition as defined in (32) which is an agent for preventing or treating cardiac disease, autoimmune disease or septic shock,
(34) Use of the compound represented by the formula (Iaa) or (Ie) for manufacturing an agent for inhibiting nitric oxide and/or cytokine production,
(35) A method for inhibiting nitric oxide and/or cytokine production in mammals which comprises administrating to a subject in need an effective amount of the compound represented by the formula (Iaa) or (Ie),
(36) Use of the compound represented by the formula (Iaa) or (Ie) for manufacturing an agent for preventing or treating cardiac disease, autoimmune disease or septic shock,
(37) A method for preventing or treating cardiac disease, autoimmune disease or septic shock in mammals which comprises administrating to a subject in need an effective amount of the compound represented by the formula (Iaa) or (Ie),
(38) A pro-drug of the compound as defined in (1) or (2),
(39) A pharmaceutical composition which contains the pro-drug as defined in (38), and so on.
In the specification, R represents an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula: OR1 (wherein R1 represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents) or a group represented by the formula: 
wherein R1b represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, R1c is, same with or different from R1b, a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, or R forms a bond with R0, and among them the group represented by the formula: OR1 (wherein R1 represents the same meaning as defined above) is preferred.
And, Ra represents an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula: OR1a (wherein R1a represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents) or a group represented by the formula: 
(wherein R1a represents the same meaning as defined above, R1b is, same with or different from R1a, a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents), or form a bond with R0a, and among them the group represented by the formula: OR1 (wherein R1 represents the same meaning as defined above) is preferred.
When R and R0 represent a bond with each other, the compound represented by the formula (Iaa) can be represented by the formula: 
wherein each symbol represents the same meanings, and specifically can be represented by the formula: 
wherein each symbol represents the same meanings, or the formula: 
wherein each symbols represents the same meanings.
When R and R0 represent a bond with each other, the compound represented by the formula (Ia) can be represented by the formula: 
wherein each symbols represents the same meanings, and specifically can be represented by the formula: 
wherein each symbols represents the same meanings, or the formula: 
wherein each symbols represents the same meanings.
When Ra and R0a represent a bond with each other, the compound represented by the formula (Ie) can be represented by the formula: 
wherein each symbols represents the same meanings, and specifically can be represented by the formula: 
wherein each symbols represents the same meanings, or the formula: 
wherein each symbols represents the same meanings.
When R is a group represented by the formula: OR1 (wherein R1 represents the same meaning as defined above), the compound represented by the formula (Iaa) can be represented by the formula: 
wherein each symbols represents the same meanings, and specifically can be represented by the formula: 
wherein each symbols represents the same meanings, or the formula: 
wherein each symbols represents the same meanings.
When R is a group represented by the formula: OR1 (wherein R1 represents the same meaning as defined above), the compound represented by the formula (Ia) can be represented by the formula: 
wherein each symbols represents the same meanings, and specifically can be represented by the formula: 
wherein each symbols represents the same meanings, or the formula: 
wherein each symbols represents the same meanings.
When Ra is a group represented by the formula: OR1a (wherein R1a represents the same meaning as defined above), the compound represented by the formula (Ie) can be represented by the formula: 
wherein each symbols represents the same meanings, and specifically can be represented by the formula: 
wherein each symbols represents the same meanings, or the formula: 
wherein each symbols represents the same meanings.
As the compound represented by the formula (Iaa), the compound represented by the formula (Icc) or the formula (Inn) is preferred, as the compound represented by the formula (Ia), the compound represented by the formula (Ic) or the formula (In) are preferred, and as the compound represented by the formula (Ie), the compound represented by the formula (Ik) or the formula (Ip) are preferred,
Similarly, the compound represented by the formula (Id) can be represented by the formula: 
wherein each symbols represents the same meanings, or the formula: 
wherein each symbols represents the same meaning, and the compound represented by the formula (Ig) can be represented by the formula: 
wherein each symbols represents the same meanings, or the formula: 
wherein each symbols represents the same meanings.
As the compound represented by the formula (Id), the compound represented by the formula (Ir) is preferred, as the compound represented by the formula (Ig), the compound represented by the formula (It) is preferred.
In the compound represented by the formula (Ia), when n is 1 or 2, and (i) R1 is a hydrogen atom or an ethyl group, R0 is a methyl group and Ar is a phenyl group, or (ii) R and R0 represent a bond with each other and Ar is a phenyl group, a 2-methylphenyl group, a 4-bromophenyl group, a 4-methoxyphenyl group or a 2,6-dimethylphenyl group, a group represented by the formula: 
is a group represented by the formula: 
Furthermore, when n is 1 to 4, and (i) R1 is a hydrogen atom or a lower alkyl group optionally having substituents, R0 is a lower alkyl group optionally having substituents, and Ar is a phenyl group optionally having substituents, or (ii) R and R0 represent a bond with each other and Ar is a phenyl group optionally having substituents, a group represented by the formula: 
may be a group represented by the formula: 
In the compound represented by the formula (Ib), when n is 1 or 2, R1 is a hydrogen atom or an ethyl group, R0 is a methyl group, and Ar is a phenyl group, a group represented by the formula: 
is a group represented by the formula: 
Furthermore, when n is 1 to 4, and R1 is a hydrogen atom or a lower alkyl group optionally having substituents, R0 is a lower alkyl group optionally having substituents, and Ar is a phenyl group optionally having substituents, a group represented by the formula: 
is a group represented by the formula: 
As the xe2x80x9caliphatic hydrocarbon groupxe2x80x9d of the xe2x80x9caliphatic hydrocarbon group optionally having substituentsxe2x80x9d represented by R, R1, R1a, R1b, R1c, and the xe2x80x9caliphatic hydrocarbon groupxe2x80x9d represented by R0, R0a, R2, R2a, for example, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an alkenyl group, an alkynyl group, etc. are preferred.
As the alkyl group, for example, a linear or branched alkyl group having 1 to 20 carbons (e.g., a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, an nonyl group, a decyl group, a dodecyl group, etc.), etc. are preferred, and particularly, for example, a lower alkyl group having 1 to 6 carbons (e.g., a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, etc.), etc. are preferred.
As the cycloalkyl group, for example, a cycloalkyl group having 3 to 10 carbons (e.g., a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, etc.), etc. are preferred, and particularly, for example, a cycloalkyl group having 3 to 6 carbons (e.g., a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, etc.), etc. are preferred.
As the cycloalkylalkyl group, for example, a cycloalkylalkyl group having 4 to 12 carbons (e.g., a cyclopropylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, a cycloheptylmethyl group, etc.), etc. are preferred, and particularly, for example, a cycloalkylalkyl group having 4 to 8 (particularly, 4 to 7) carbons (e.g., a cyclopropylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, etc.), etc. are preferred.
As the alkenyl group,for example, a lower alkenyl group having 3 to 6 carbons (e.g., a propenyl group, a butenyl group, a pentenyl group, etc.), and particularly, for example, a lower alkenyl group having 3 or 4 carbons (e.g., a propenyl group, a butenyl group, etc.), etc. are preferred.
As the alkynyl group,for example, a lower alkynyl group having 3 to 6 carbons (e.g., a propynyl group, a butynyl group, a pentynyl group, etc.), and particularly, for example, a lower alkenyl group having 3 or 4 carbons (e.g., a propynyl group, a butynyl group, etc.), etc. are preferred.
As the xe2x80x9csubstituentsxe2x80x9d of the above mentioned xe2x80x9caliphatic hydrocarbon group optionally having substituentsxe2x80x9d, for example, a heterocyclic group, an oxo group, a hydroxy group, a C1-6 alkoxy group, a C3-10 (particularly, C3-6) cycloalkyloxy group, a C6-10 aryloxy group, a C7-19 (particularly, C7-12) aralkyloxy group, a heterocyclic oxy group, a C1-6 alkylthio group (the sulfur atom may be oxidized), a C3-10 (particularly, C3-6) cycloalkylthio group (the sulfur atom may be oxidized), a C6-10 arylthio group (the sulfur atom may be oxidized), a C7-19 (particularly, C7-12) aralkyloxy group (the sulfur atom may be oxidized), a heterocyclic thio group, a heterocyclic sulfinyl group, a heterocyclic sulfonyl group, a nitro group, a halogen atom, a cyano group, a carboxyl group, a C1-10 (particularly, C1-6) alkoxy-carbonyl group, a C3-6 cycloalkyloxy-carbonyl group, a C6-10 aryloxy-carbonyl group, a C7-19 (particularly, C7-12) aralkyloxy-carbonyl group, a heterocyclic oxycarbonyl group, a C6-10 aryl-carbonyl group, C1-6 alkanoyl group, C3-5 alkenoyl group, a C6-10 aryl-carbonyloxy group, a C2-6 alkanoyloxy group, a C3-5 alkenoyloxy group, a carbamoyl group optionally having substituents, a thiocarbamoyl group optionally having substituents, a carbamoyloxy group optionally having substituents, a C1-6 alkanoylamino group, a C6-10 aryl-carbonylamino group, a C1-10 (particularly, C1-6) alkoxy-carboxamide group, a C6-10 aryloxy-carboxamide group, a C7-19 (particularly, C7-12) aralkyloxy-carboxamide group, a C1-10 (particularly, C1-6) alkoxy-carbonyloxy group, a C6-10 aryloxy-carbonyloxy group, a C7-19 (particularly, C7-12) aralkyloxy-carbonyloxy group, a C3-10 particularly, C3-6)cycloalkyloxy-carbonyloxy group, an ureido group optionally having substituents, a C6-10 aryl group optionally having substituents, etc. are used.
These substituents are substituted at substitutable positions in the above mentioned xe2x80x9caliphatic hydrocarbon groupxe2x80x9d, and the substituents are not limited to one and may be same or different and a few numbers (2 to 4).
As the xe2x80x9cC1-6 alkoxy groupxe2x80x9d, for example, a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, a tert-butoxy group, a n-pentyloxy group, a n-hexyloxy group, etc. are used, as the xe2x80x9cC3-10 cycloalkyloxy groupxe2x80x9d, for example, a cyclopropyloxy group, a cyclohexyloxy group, etc. are used, as the xe2x80x9cC6-10 aryloxy groupxe2x80x9d, for example, a phenoxy group, a naphthyloxy group, etc. are used, as the xe2x80x9cC7-19 aralkyloxy groupxe2x80x9d, for example, a benzyloxy group, a 1-phenylethyloxy group, a 2-phenylethyloxy group, a benzhydryloxy group, a 1-naphthylmethyloxy group, etc. are used, as the xe2x80x9cC1-6 alkylthio group (the sulfur atom may be oxidized)xe2x80x9d, for example, a methylthio group, an ethylthio group, a n-propylthio group, a n-butylthio group, a methylsulfinyl group, a methylsulfonyl group, etc. are used, as the xe2x80x9cC3-10 cycloalkylthio group (the sulfur atom may be oxidized)xe2x80x9d, for example, a cyclopropylthio group, a cyclohexylthio group, a cyclopentylsulfinyl group, a cyclohexylsulfonyl group, etc. are used, as the xe2x80x9cC6-10 arylthio group (the sulfur atom may be oxidized)xe2x80x9d, for example, a phenylthio group, a naphthylthio group, a phenylsulfinyl group, a phenylsulfonyl group, etc. are used, as the xe2x80x9cC9-19 aralkylthio group (the sulfur atom may be oxidized)xe2x80x9d, for example, a benzylthio group, a phenylethylthio group, a benzhydrylthio group, a benzylsulfinyl group, a benzylsulfonyl group, etc. are used, as the xe2x80x9chalogen atomxe2x80x9d, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc. are used, as the xe2x80x9cC1-10 alkoxy-carbonyl groupxe2x80x9d, for example, a methoxycarbonyl group, an ethoxycarbonyl group, a n-propoxycarbonyl group, an isopropoxycarbonyl group, a n-butoxycarbonyl group, a isobutoxycarbonyl group, a tert-butoxycarbonyl group, etc. are used, as the xe2x80x9cC3-6 cycloalkyloxycarbonyl groupxe2x80x9d, for example, a cyclopropyloxycarbonyl group, a cyclopentyloxycarbonyl group, a cyclohexyloxycarbonyl group, a norbornyloxycarbonyl group, etc. are used, as the xe2x80x9cC6-10 aryloxy-carbonyl groupxe2x80x9d, for example, a phenoxycarbonyl group, a naphthyloxycarbonyl group, etc. are used, as the xe2x80x9cC7-19 aralkyl-oxycarbonyl groupxe2x80x9d, for example, a benzyloxycarbonyl group, a benzhydryloxycarbonyl group, a 2-phenethyloxycarbonyl group, etc. are used, as the xe2x80x9cC6-10 aryl-carbonyl groupxe2x80x9d, for example, a benzoyl group, a naphthoyl group, a phenylacetyl group, etc. are used, as the xe2x80x9cC1-6 alkanoyl groupxe2x80x9d, for example, a formyl group, an acetyl group, a propionyl group, a butyryl group, a valeryl group, a pivaloyl group, etc. are used, as the xe2x80x9cC3-5 alkenoyl groupxe2x80x9d, for example, an acryloyl group, a crotonoyl group, etc. are used, as the xe2x80x9cC6-10 aryl-carbonyloxy groupxe2x80x9d, for example, a benzoyloxy group, a naphthoyloxy group, a phenylacetoxy group, etc. are used, as the xe2x80x9cC2-6 alkanoyloxy groupxe2x80x9d, for example, an acetoxy group, a propionyloxy group, a butyryloxy group, a valeryloxy group, a pivaloyloxy group, etc. are used, as the xe2x80x9cC3-5 alkenoyl groupxe2x80x9d, for example, an acryloyloxy group, a crotonoyloxy group, etc. are used.
As the xe2x80x9ccarbamoyl group optionally having substituentsxe2x80x9d, for example, a carbamoyl group or a cyclicaminocarbonyl group, which may be substituted by 1 or 2 substituents selected from C1-4 alkyl (e.g., methyl, ethyl, etc.), phenyl, C1-7 acyl (e.g., acetyl, propionyl, benzoyl, etc.), C1-4 alkoxy-phenyl (e.g., methoxyphenyl, etc.), etc. and specifically for example a carbamoyl group, a N-methylcarbamyl group, a N-ethylcarbamoyl group, a N,N-dimethylcarbamoyl group, a N,N-diethylcarbamoyl group, a N-phenylcarbamoyl group, a N-acetylcarbamoyl group, a N-benzoylcarbamoyl group, a N-(p-methoxyphenyl)carbamoyl group, a 1-pyrrolydinylcarbonyl group, a piperazinocarbonyl group, a 1-piperazinylcarbonyl group, a morpholinocarbamoyl group, etc. are used.
As the xe2x80x9cthiocarbamoyl group optionally having substituentsxe2x80x9d, for example, a thiocarbamoyl group which may be substituted by 1 or 2 substituents selected from C1-4 alkyl (e.g., methyl, ethyl, etc.), phenyl, etc. and specifically for example a thiocarbamoyl group, a N-methylthiocarbamoyl group, a N-phenylthiocarbamoyl group, etc. are used.
As the xe2x80x9ccarbamoyloxy group optionally having substituentsxe2x80x9d, for example, a carbamoyloxy group which may be substituted by 1 or 2 substituents selected from C1-4 alkyl (e.g., methyl, ethyl, etc.), phenyl, etc. and specifically for example a carbamoyloxy group, a N-methylcarbamoyloxy group, a N,N-dimethylcarbamoyloxy group, a N-ethylcarbamoyloxy group, a N-phenylcarbamoyloxy group, etc. are used.
As the xe2x80x9cC1-6 alkanoylamino groupxe2x80x9d, for example, an acetoamide group, a propionamide group, a butyroamide group, a valeroamide group, a pivaloamide group, etc. are used, as the xe2x80x9cC6-10 aryl-carbonylamino groupxe2x80x9d, for example, a benzamide group, a naphthoamide group, a phthalimide group, etc. are used, as the xe2x80x9cC1-10 alkoxy-carboxamide groupxe2x80x9d, for example, a methoxycarboxamide (CH3OCONHxe2x80x94) group, an ethoxycarboxamide group, a tert-butoxycarboxamide group, etc. are used, as the xe2x80x9cC6-10 aryloxy-carboxamide groupxe2x80x9d, for example, a phenoxycarboxamide (C6H5OCONHxe2x80x94) group, etc. are used, as the xe2x80x9cC7-10 aralkyloxy-carboxamide groupxe2x80x9d, for example, a benzyloxycarboxamide (C6H5CH2OCONHxe2x80x94) group, a benzhydryloxycarboxamide group, etc. are used, as the xe2x80x9cC1-10 alkoxy-carbonyloxy groupxe2x80x9d, for example, a methoxycarbonyloxy group, an ethoxycarbonyloxy group, a n-propoxycarbonyloxy group, an isopropoxycarbonyloxy group, a n-butoxycarbonyloxy group, a tert-butoxycarbonyloxy group, a n-pentyloxycarbonyloxy group, a n-hexyloxycarbonyloxy group, etc. are used, as the xe2x80x9cC6-10 aryloxy-carbonyloxy groupxe2x80x9d, for example, a phenoxycarbonyloxy group, a naphthyloxycarbonyloxy group, etc. are used, as the xe2x80x9cC2-19 aralkyloxy-carbonyloxy groupxe2x80x9d, for example, a benzyloxycarbonyloxy group, a 1-phenylethyloxycarbonyloxy group, a 2-phenylethyloxycarbonyloxy group, a benzhydryloxycarbonyloxy group, etc. are used, and as the xe2x80x9cC3-10 cycloalkyloxy-carbonyloxy groupxe2x80x9d, for example, a cyclopropyloxycarbonyloxy group, a cyclohexyloxycarbonyloxy group, etc. are used.
As the xe2x80x9cureido group optionally having substituentsxe2x80x9d, for example, an ureido group optionally substituted by 1 to 3 substituents selected from a C1-4 alkyl group (e.g., a methyl group, an ethyl group, etc.), a phenyl group, etc. are used, and for example an ureido group, a 1-methylureido group, a 3-methylureido group, a 3,3-dimethylureido group, a 1,3-dimethylureido group, a 3-phenylureido group, etc. used.
When a heterocyclic group, a heterocyclic oxy group, a heterocyclic thio group, a heterocyclic sulfinyl group, a heterocyclic sulfonyl group or a heterocyclicoxycarbonyl group are used as the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9caliphatic hydrocarbon group optionally having substituentsxe2x80x9d, the heterocyclic group represents a group formed by excluding one hydrogen atom which binds to the heterocycle, and it represents, for example, a 5- to 8-membered cyclic (preferably 5- to 6-membered cyclic) group containing 1 to a few, preferably 1 to 4 hetero atoms such as a nitrogen atom (optionally oxidized), an oxygen atom, a sulfur atom, etc., or a condensed cyclic group thereof. As these heterocyclic groups, for example, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a 1,2,3-triazolyl group, a 1,2,4-triazolyl group, a tetrazolyl group, a furyl group, a thienyl group, an oxazolyl group, an isooxazolyl group, a 1,2,3-oxadiazolyl group, a 1,2,4-oxadiazolyl group, a 1,2,5-oxadiazolyl group, a 1,3,4-oxadiazolyl group, a thiazolyl group, an isothiazolyl group, a 1,2,3-thiadiazolyl group, a 1,2,4-thiadiazolyl group, a 1,2,5-thiadiazolyl group, a 1,3,4-thiadiazolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, an indolyl group, a pyranyl group, a thiopyranyl group, a dioxynyl group, a dioxolyl group, a quinolyl group, a pyrido[2,3-d]pyrimidinyl group, 1,5-, 1,6-, 1,7-, 1,8-, 2,6- or 2,7-naphthyridyl group, a thieno[2,3-d]pyridyl group, a benzopyranyl group, a tetrahydrofuryl group, a tetrahydropyranyl group, a dioxolanyl group, a dioxanyl group, etc. are used.
These heterocyclic groups may be substituted at possible positions by 1 to 3 substituents selected by from C1-4 alkyl (e.g., methyl, ethyl, etc.), hydroxy, oxo, C1-4 alkoxy (e.g., methoxy, ethoxy, etc.), etc.
As the xe2x80x9cC6-10 aryl groupxe2x80x9d the xe2x80x9cC6-10 aryl group optionally having substituentsxe2x80x9d, for example, a phenyl group, a naphthyl group, etc. are used. The C6-10 aryl group may be substituted at a substitutable position by a substituent selected from the those listed as a xe2x80x9csubstituentxe2x80x9d (except for an optionally substituted C6-10 aryl group) of the xe2x80x9caliphatic hydrocarbon optionally having substituentsxe2x80x9d described above. Such a substituent is substituted at a substitutable position in a C6-10 aryl group, and the number of such substituents is not limited to one, and, the same or different, more than one (2 to 4) substituents may exist.
In the xe2x80x9caliphatic hydrocarbon group optionally having substituentsxe2x80x9d, the substituent together with the aliphatic hydrocarbon group may form an optionally substituted fused ring group, and as these condensed ring groups, an indanyl group, a 1,2,3,4-tetrahydronaphthyl group, etc. are used. This condensed ring group may be substituted at a substitutable position by a substituent selected from the those listed as a xe2x80x9csubstituentxe2x80x9d of the xe2x80x9caliphatic hydrocarbon optionally having substituentsxe2x80x9d described above. Such a substituent is substituted at a substitutable position in a fused ring group, and the number of such substituents is not limited to one, and, the same or different, more than one (2 to 4) substituents may exist.
As R, R1, R1a, R1b, R1c, for example, a lower alkyl group having 1 to 6 carbon atoms (e.g., a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a t-butoxycarbonylmethyl group, a hydroxyethyl group and the like) optionally having substituents, and of them a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, etc. are preferably used. Particularly, a methyl group, an ethyl group, a n-propyl group and the like, etc. are prefered, and an ethyl group is preferred particularly.
As R2, R2a, for example, a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms (e.g., a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a t-butoxycarbonylmethyl group, a hydroxyethyl group and the like), etc. are preferably used, and a hydrogen atom, a methyl group, etc. are preferably used and particularly a hydrogen atom, etc. are preferably used.
As the xe2x80x9caromatic hydrocarbon groupxe2x80x9d of the xe2x80x9caromatic hydrocarbon group optionally having substituentsxe2x80x9d represented by Ar, Ara, for example, an aromatic hydrocarbon group having 6 to 14 carbon atoms (e.g., a phenyl group, a naphthyl group, a biphenyl group, an anthryl group, an indenyl group and the like) and the like, and particularly an aryl group having 6 to 10 carbon atoms and the like (e.g., phenyl and naphthyl groups) are preferred and a phenyl group and the line are particularly preferred.
As the xe2x80x9csubstituentxe2x80x9d of the xe2x80x9caromatic hydrocarbon group optionally having substituentsxe2x80x9d represented by Ar, Ara, for example, a halogen atom (e.g., fluorine, chlorine, bromine, iodine and the like), a lower (C1-4) alkyl group (e.g., a methyl group, an ethyl group, a propyl group, a butyl group and the like), a lower (C1-4) alkoxy group (e.g., a methoxy group, an ethoxy group, a propoxy group, a butoxy group and the like), a lower (C1-4) alkoxycarbonyl group (e.g., a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group and the like), a carboxyl group, a nitro group, a cyano group, a hydroxyl group, an acylamino group (e.g., an alkanoylamino group having 1 to 4 carbon atoms such as an acetylamino group, a propionylamino group, a butyrylamino group and the like), a cycloalkyl group having 3 to 6 carbon atoms (e.g., a cyclopropyl group, a cyclopentyl group and the like), an aryl group having 6 to 10 carbon atoms (e.g., a phenyl group, a naphthyl group, an indenyl group and the like), a halogeno-lower (C1-4) alkyl group (e.g., a trifluoromethyl group, a trifluoroethyl group and the like), a halogeno-lower (C1-4) alkoxy group (e.g., a trifluoromethoxy group, a 1,1,2,2-tetrafluoroethoxy group, a 2,2,3,3,3-pentafluoropropoxy group and the like), a lower (C1-4) alkylthio group (e.g., a methylthio group, an ethylthio group, a propionylthio group and the like), a lower (C1-4) alkylsulfonyl group (e.g., a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group and the like), a lower (C1-4) alkanoyl group (e.g., a formyl group, an acetyl group, a propionyl group and the like), a 5-membered aromatic heterocyclic group (e.g., a 1,2,3-triazolyl group, a 1,2,4-triazolyl group, a tetrazolyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, an isooxyazolyl group, a thiadiazolyl group, a thienyl group, a furyl group and the like), a carbamoyl group, a lower (C1-4) alkyl-carbamoyl group (e.g., a methylcarbamoyl group, a dimethylcarbamoyl group, a propionylcarbamoyl group and the like), a lower (C1-4) alkoxy-carbonyl-lower (C1-4) alkyl-carbamoyl group (e.g., a butoxycarbonylmethylcarbamoyl group, an ethoxycarbonylmethylcarbamoyl group and the like), a 1,3-diacylguanidino-lower (C1-4) alkyl group and the like (e.g., 1,3-diacetylguanidinomethyl, 1,3-bis-t-butoxycarbonylguanidinomethyl and the like) are used, and a halogen atom (e.g., fluorine, chlorine, bromine, iodine atoms and the like), a lower (C1-4) alkyl group and the like (e.g., a methyl group, an ethyl group, a propyl group, a butyl group and the like) are preferably used, and a fluorine atom, a chlorine atom and a methyl group are more preferably used.
These substituents are substituted at substitutable positions in the aromatic hydrocarbon group, and the number of the substituents is preferably 1 to 5, more preferably 1 to 3, most preferably 1 to 2. When two or more of such substituents are present, they may be the same or different.
Typically, as Ar or Ara, for example, a phenyl group, a halogenophenyl group, a lower (C1-4) alkylphenyl group, a lower (C1-4) alkoxyphenyl group, a lower (C1-4) alkoxycarbonylphenyl group, a carboxylphenyl group, a nitrophenyl group, a cyanophenyl group, a halogeno-lower (C1-4) alkylphenyl group, a halogeno-lower (C1-4) alkoxyphenyl group, a lower (C1-4) alkanoylphenyl group, a 5-membered aromatic heterocycle-substituted phenyl group, a lower (C14) alkoxy-carbonyl-lower (C1-4) alkyl-carbamoylphenyl group, 1,3-diacylguanidino-lower (C1-4) alkylphenyl group, a halogen- and lower (C1-4) alkoxy-substituted phenyl a group, a halogen- and lower (C1-4) alkoxycarbonyl-substitutedphenyl group, a halogen- and cyano-substituted phenyl group, a halogen- and 5-membered aromatic heterocycle-substituted phenyl group, a halogen- and lower (C1-4) alkoxycarbonyl-lower (C1-4) alkyl-carbamoyl-substituted phenyl group and the like are used.
As Ar or Ara, a halogenophenyl group, a lower (C1-4) alkylphenyl group, a halogen- and lower (C1-4) alkoxycarbonyl-substituted phenyl and the like are preferably used.
As Ar or Ara, a group represented by formula: 
wherein R4 and R5 is the same or different and each represents a halogen atom or a lower alkyl group, and n is an integer of 0 to 2, with one in which at least one of R4 and R5 is a halogen atom being further preferred.
As the halogen atom represented by R4 and R5, a fluorine atom or a chlorine atom is preferred.
As the halogenophenyl group, for example, a 2,3-difluorophenyl group, a 2,3-dichlorophenyl group, a 2,4-difluorophenyl group, a 2,4-dichlorophenyl group, a 2,5-difluorophenyl group, a 2,5-dichlorophenyl group, a 2,6-difluorophenyl group, a 2,6-dichlorophenyl group, a 3,4-difluorophenyl group, a 3,4-dichlorophenyl group, a 3,5-difluorophenyl group, a 3,5-dichlorphenyl group, a 2-fluorophenyl group, a 2-chlorophenyl group, a 3-fluorophenyl group, a 3-chlorophenyl group, a 4-fluorophenyl group, a 4-chlorophenyl group, a 2-fluoro-4-chlorophenyl group, a 2-chloro-4-fluorophenyl group, a 4-bromo-2-fluorophenyl group, a 2,3,4-trifluorophenyl group, a 2,4,5-trifluorophenyl group, a 2,4,6-trifluorohenyl group and the like are used.
As the lower (C1-4) alkylphenyl group, a 2-ethylphenyl group, a 2,6-diisopropylphenyl group and the like are preferably used, and as the lower (C1-4) alkoxyphenyl group, for example, a 4-methoxyphenyl group and the like are preferably used.
As the halogenophenyl group, for example, a 2,3-difluorophenyl group, a 2,3-dichlorophenyl group, a 2,4-difluorophenyl group, a 2,4-dichlorophenyl group, a 2,5-difluorophenyl group, a 2,5-dichlorophenyl group, a 2,6-difluorophenyl group, a 2,6-dichlorophenyl group, a 3,4-difluorophenyl group, a 3,4-dichlorophenyl group, a 3,5-difluorophenyl group, a 3,5-dichlorophenyl group, a 2-fluorophenyl group, a 2-chlorophenyl group, a 3-fluorophenyl group, a 3-chlorophenyl group, a 4-fluorophenyl group, a 4-chlorophenyl group, a 2-fluoro-4-chlorophenyl group, a 2-chloro-4-fluorophenyl group, a 4-bromo-2-fluorophenyl group, a 2,3,4-trifluorophenyl group, a 2,4,5-trifluorophenyl group, a 2,4,6-trifluorophenyl group and the like are used.
As the lower (C1-4) alkanoylphenyl group, for example, a 2-acetylphenyl group and the like are preferably used, and as the 5-membered aromatic heterocycle-substituted phenyl, for example, a 4-(2H-1,2,3-triazol-2-yl)phenyl group, a 4-(2H-tetrazol-2-yl)phenyl group, a 4-(1H-tetrazol-1-yl)phenyl group, a 4-(1H-1,2,3-triazol-1-yl)phenyl group and the like are preferably used, and as the lower (C1-4) alkoxy-carbonyl-lower (C1-4) alkyl-carbamoylphenyl group, for example, a 4-(N-ethoxycarbonylmethylcarbamoyl)phenyl group and the like are preferably used, and as the 1,3-diacylguanidino-lower (C1-4) alkylphenyl group, for example, a 4-(1,3-bis-t-butoxycarbonylguanidinomethyl)phenyl group and the like are preferably used.
As the phenyl group substituted by halogen and lower (C1-4) alkyl, for example, a 2-fluoro-4-methylphenyl group, a 2-chloro-4-methylphenyl group, a 4-fluoro-2-methylphenyl group and the like are preferably used, and as the phenyl group substituted by halogen and lower (C1-4) alkoxycarbonyl, for example, a 2-chloro-4-methoxycarbonylphenyl group and the like are preferably used, and the phenyl group substituted by halogen and cyano, for example, a 2-chloro-4-cyanophenyl group and the like are preferably used, and as the phenyl group substituted by halogen and 5-membered aromatic heterocycle, for example, a 2-fluoro-4-(1H-1,2,4-triazol-1-yl)phenyl group and the like are preferably used, and as the phenyl group substituted by halogen and lower (C1-4) alkoxycarbonyl-lower (C1-4) alky-carbamoyl, for example, a 2-chloro-4-(N-t-butoxycarbonylmethylcarbamoyl)phenyl group, a 2-chloro-4-(N-ethoxycarbonylmethylcarbamoyl)phenyl group and the like are preferably used.
More specifically, as Ar or Ara, a phenyl group, a phenyl group substituted with 1 to 3 (particularly 1 to 2) halogen atoms (e.g., a 2,3-difluorophenyl group, a 2,3-dichlorophenyl group, a 2,4-difluorophenyl group, a 2,4-dichlorophenyl group, a 2,5-difluorophenyl group, a 2,5-dichlorophenyl group, a 2,6-difluorophenyl group, a 2,6-dichlorophenyl group, a 3,4-difluorophenyl group, a 3,4-dichlorophenyl group, a 3,5-difluorophenyl group, a 3,5-dichlorophenyl group, a 4-bromo-2-fluorophenyl group, a 2-fluorophenyl group, a 2-chlorophenyl group, a 3-fluorophenyl group, a 3-chlorophenyl group, a 4-fluorophenyl group, a 4-chlorophenyl group, a2-fluoro-4-chlorophenyl group, a 2-chloro-4-fluorophenyl group, a 2,3,4-trifluorophenyl group, a 2,4,5-trifluorophenyl group and the like), a phenyl group substituted by halogen and lower (C1-4) alkyl (e.g., a 2-chloro-4-methylphenyl group, a 4-fluoro-2-methylphenyl group and the like), etc. are preferred. Of them, a phenyl group substituted with 1 to 3 (particularly 1 to 2) halogen atoms (e.g., a 2,3-dichlorophenyl group, a 2,4-difluorophenyl group, a 2,4-dichlorophenyl group, a 2,6-dichlorophenyl group, a 2-fluorophenyl group, a 2-chlorophenyl group, a 3-chlorophenyl group, a 2-chloro-4-fluorophenyl group, a 2,4,5-trifluorophenyl group and the like), a phenyl group substituted by halogen and lower (C1-4) alkyl (e.g., a 2-chloro-4-methylphenyl group, a 4-fluoro-2-methylphenyl group and the like), etc. are preferred. Particularly, a 2,4-difluorophenyl group, a 2-chlorophenyl group, a 2-chloro-4-fluorophenyl group, a 2-chloro-4-methylphenyl group and the like are preferred, and a 2,4-difluorophenyl group, a 2-chloro-4-fluorophenyl group and the like are preferred.
In this specification, the ring A represents (i) an aliphatic hydrocarbon group optionally having substituents, (ii) an aromatic hydrocarbon group optionally having substituents, (iii) a group represented by formula OR1 (wherein R1 is as defined above) and (iv) a cycloalkene substituted by 1 to 4 halogen atoms, and (i) an aliphatic hydrocarbon group optionally having substituents, (ii) an aromatic hydrocarbon group optionally having substituents and (iv) a cycloalkene substituted by 1 to 4 halogen atoms are preferred.
These substituents are substituted on substitutable carbon atoms in a ring A, and when the ring A is substituted by two or more of such substituents, the substituents may be the same or different. A single carbon atom may be substituted by two substituents and different carbon atoms may be substituted by two or more substituents.
As the xe2x80x9caliphatic hydrocarbon group optionally having substituentsxe2x80x9d as a substituent on the ring A, for example, the same those as the xe2x80x9caliphatic hydrocarbon group optionally having substituentsxe2x80x9d represented by R, R1, R1a, R1b, R1c described above may be used.
As the xe2x80x9caromatic hydrocarbon group optionally having substituentsxe2x80x9d as a substituent on the ring A, for example, the same those as the xe2x80x9caromatic hydrocarbon group optionally having substituentsxe2x80x9d represented by Ar or Ara described above may be used.
As the xe2x80x9cheterocyclic group optionally having substituentsxe2x80x9d as a substituent on the ring, for example, the same thise as the xe2x80x9cheterocyclic groupxe2x80x9d which is a xe2x80x9csubstituentxe2x80x9d on the xe2x80x9caliphatic hydrocarbon group optionally having substituentsxe2x80x9d represented by R, R1, R1a, R1b, R1c.
As the substituents for the ring A, 1 or 2 C1-6 alkyl group (e.g., a C1-4 alkyl group such as a methyl group, a tert-butyl group, etc.), a phenyl group, a halogen atom (e.g., florine, chlorine, bromine, iodine, etc.), etc. are preferably used.
The group represented by the formula: 
wherein n represents the same meaning as defined above, represents a group represented by the formula: 
wherein n represents the same meaning as defined above, and preferably a group represented by the formula: 
The group represented by the formula: 
wherein n represents the same meaning as defined above, represents a group represented by the formula: 
wherein n represents the same meaning as defined above, and preferably a group represented by the formula: 
And, the group represented by the formula: 
represents a group represented by the formula: 
and preferably a group represented by the formula: 
As the integer of 1 to 4 represented by n, 1 to 3 is preferred and 2 is more preferred.
As the compound represented by the formula (Iaa), the compound represented by the formula (Ibb) is preferred, and as the compound represented by the formula (Ia), the compound represented by the formula (Ib) is preferred.
As the compound represented by the formula (Ibb), the compound represented by the formula (Inn) is preferred, and as the compound represented by the formula (Ib), the compound represented by the formula (In) is preferred.
As the compound (Ibb), (Ib), a compound wherein R1 is a lower alkyl group optionally having substituents, R2 is a hydrogen atom or a lower alkyl group, Ar is a phenyl group optionally having substituents, n is 1, 2 or 3 is preferred, and a compound wherein R1 is a lower alkyl group optionally having substituents, R2 is a hydrogen atom, Ar is a phenyl group substituted by a halogen atom, n is 2 is more preferred,
As the compound represented by the formula (Icc), (Ic), a compound wherein Ar is a phenyl group optionally having substituents, n is 2 is preferred.
As the leaving group represented by X1, for example, a halogen atom (e.g., chlorine, bromine, iodine, etc.), etc. are preferred and a chlorine atom is more preferred.
When the compounds represented by formulae (Iaa), (Ibb), (Icc), (Ia), (Ib), (Ic), (Id), (Ie), (If) and (Ig) have stereoisomers, any of such stereoisomers and mixtures thereof are included in the invention.
When a compound represented by formula (Iaa) is a compound represented by formula (Icc) or (Inn), when a compound represented by formula (Ia) is a compound represented by formula (Ic) or (In), when a compound represented by formula (Ie) is a compound represented by formula (Ik) or (Ip), when a compound represented by formula (Id) is a compound represented by formula (Ir), and when a compound represented by formula (Ig) is a compound represented by formula (It), then each compound can exist as an optical isomer with regard to the asymmetric carbon atom in a cycloalkene or cyclohexene ring, and any of such optical isomers and mixtures thereof are included in the invention.
A compound represented by formula (Ia) may preferably be d-ethyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate, ethyl 6-[N-(2-chlorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate, ethyl 6-[N-(2-chloro-4-methylphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate or d-ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate as well as a salt thereof.
In the above mentioned formulae, methods for producing a compound represented by the formula: 
wherein n is 1 or 2, and a compound represented by the formula: 
wherein n is 1 or 2, are reported in Journal of American Chemical Society, Vol.101, pp6981-6991 (1979).
And, a method for producing a compound represented by the formula: 
wherein Arb is a phenyl group, a 2-methylphenyl group, a 4-bromophenyl group, a 4-methoxyphenyl group or a 2,6-dimethylphenyl group, is reported in Tetrahedron, Vol.52, pp783-790 (1996).
A method for producing an inventive compound (Ia), (Ib) or (Ic) or a salt thereof is discussed below.
While the following description of a production method may be applicable not only to an inventive compound (Ia), (Ib) or (Ic) but also to a salt thereof, the following description may sometimes employ a simple expression, i.e, Compound (Ia), (Ib) or (Ic). An inventive compound (Iaa), (Ibb) or (Icc) or a salt thereof can also be produced similarly.
While a method for producing Compound (Ia) wherein R is represented by formula OR1 wherein R1 is as defined above is described below, a compound wherein R is an optionally substituted aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon group, an optionally substituted heterocyclic group, a group represented by the formula: 
wherein each symbol is as defined above may also be produced similarly.
Compound (Ia) of the invention wherein R is represented by the formula OR1 wherein R1 is as defined above and R0 is a hydrogen atom or an aliphatic hydrocarbon group, i.e., Compound (Ib), typically Compounds (In) and (Io) can, for example, be produced by reacting a compound represented by the formula: 
wherein each symbol is as defined above or a salt thereof with a compound represented by the formula: 
wherein each symbol is as defined above or a salt thereof, or by subjecting a product obtained by a reaction of Compound (IIa) or a salt thereof with Compound (IIIa) or a salt thereof to a hydrolysis known per se.
During the process of the reaction of Compound (IIa) with Compound (IIIa), a group of Compound (IIa) represented by the formula: 
wherein n is as defined above may be isomerized into a group represented by the formula: 
wherein n is as defined above, resulting in the production of a compound (Ib) wherein a group represented by the formula: 
wherein n is as defined above is a group represented by the formula: 
wherein n is as defined above, i.e., a compound represented by the formula (In).
A reaction of Compound (IIa) or a salt thereof with Compound (IIIa) or a salt thereof can be performed in the absence or presence of a base in a solvent which does not affect the reaction adversely or using no solvent. In this reaction, the amount of Compound (IIIa) or a salt used is preferably about 1 to about 5 times (molar ratio), more preferably about 1 to about 2 times (molar ratio) that of Compound (IIa) or a salt thereof. The base which can be employed may, for example, be an inorganic base (e.g., sodium hydride, potassium hydride, sodium hydroxide and the like), an organic base (e.g., triethylamine, pyridine, diisopropylethylamine and the like), preferably an organic base such as triethylamine. The amount of a base, when used, is preferably about 0.5 to about 5 times (molar ratio), more preferably about 0.9 to about 2 times (molar ratio) that of Compound (IIa).
A solvent employed in the reaction of Compound (IIa) with Compound (IIIa) which does not affect the reaction adversely may, for example, be a sulfoxide (e.g., dimethyl sulfoxide and the like), an ether (e.g., diethyl ether, tetrahydrofuran, dioxane and the like), a nitrile (e.g., acetonitrile and the like), an aromatic hydrocarbon (e.g., benzene, toluene, xylene and the like), a halogenated hydrocarbon (e.g., dichloromethane, chloroform, 1,2-dichloroethane and the like), an ester (e.g., ethyl acetate), an amide (e.g., dimethylformamide, acetamide, dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidone and the like) and the like. Any of these solvent may be employed alone or in combination of two or more in an appropriate ratio.
A reaction of Compound (IIa) with Compound (IIIa) is performed at a temperature preferably of about xe2x88x9210xc2x0 C. to 100xc2x0 C., more preferably about 0xc2x0 C. to 60xc2x0 C. The reaction times range from about 0.5 to about 50 hours, preferably about 0.5 hours to about 30 hours.
Compound (In) and Compound (Io) which are the products of this reaction may be produced each as a single compound or in a mixture. When R2 in Compound (Io) is a hydrogen atom, a ring closure reaction may proceed under some reaction and/or isolation conditions, resulting in a compound represented by the formula (Ii).
Compound (Ib) of the invention wherein R2 is an xe2x80x9coptionally substituted aliphatic hydrocarbon groupxe2x80x9d can, for example, be produced by reacting a compound represented by the formula: 
wherein each symbol is as defined above or a salt thereof with a compound represented by the formula:
R2bxe2x80x94X2xe2x80x83xe2x80x83(IIIb)
wherein X2 is a leaving group (e.g., a halogen atom (e.g., chlorine, bromine, iodine atoms and the like) or a group represented by the formula xe2x80x94O3SR3 wherein R3 is a lower alkyl group having 1 to 4 carbon atoms or an optionally substituted phenyl group, and R2b is an optionally substituted aliphatic hydrocarbon group and the like, or by subjecting a product obtained by a reaction of Compound (Ix) or a salt thereof with Compound (IIIa) or a salt thereof to a hydrolysis known per se.
A reaction of Compound (Ix) or a salt thereof with Compound (IIIb) can be performed in the absence or presence of a base in a solvent which does not affect the reaction adversely or using no solvent. In this reaction, the amount of Compound (IIIb) used is preferably about 1 to about 5 times (molar ratio), more preferably about t to about 2 times (molar ratio) that of Compound (Ix). The base which can be employed may, for example, be an inorganic base (e.g., potassium carbonate, sodium hydride, potassium hydride, sodium hydroxide and the like), an organic base (e.g., triethylamine, pyridine, diisopropylethylamine and the like). The amount of a base, when used, is preferably about 0.5 to about 5 times (molar ratio), more preferably about 0.9 to about 2 times (molar ratio) that of Compound (Ix).
A solvent employed in the reaction of Compound (Ix) with Compound (IIIb) which does not affect the reaction adversely may, for example, be a sulfoxide (e.g., dimethyl sulfoxide and the like), an ether (e.g., diethyl ether, tetrahydrofuran, dioxane and the like), a nitrile (e.g., acetonitrile and the like), an aromatic hydrocarbon (e.g., benzene, toluene, xylene and the like), a halogenated hydrocarbon (e.g., dichloromethane, chloroform, 1,2-dichloroethane and the like), an ester (e.g., ethyl acetate), an amide (e.g., dimethylformamide, acetamide, dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidone and the like) and the like. Any of these solvent may be employed alone or in combination of two or more in an appropriate ratio.
A reaction of Compound (Ix) with Compound (IIb) is performed at a temperature preferably of about xe2x88x9210xc2x0 C. to 100xc2x0 C., more preferably about 0xc2x0 C. to 60xc2x0 C. The reaction times range from about 0.1 to about 50 hours, preferably about 0.5 hours to about 10 hours.
Compound (Ib) of the invention wherein R1 is an xe2x80x9coptionally substituted aliphatic hydrocarbon groupxe2x80x9d can, for example, be produced by reacting a compound represented by the formula: 
wherein M is a hydrogen atom or an alkaline metal (e.g., lithium, sodium, potassium and the like, and each of the other symbols is as defined above or a salt thereof with a compound represented by the formula:
R1xe2x80x94X2xe2x80x83xe2x80x83(IIIc)
wherein each symbol is as defined above or a salt thereof.
A reaction of Compound (Iy) with Compound (IIIc) can be performed in the absence or presence of a base in a solvent which does not affect the reaction adversely or using no solvent. In this reaction, the amount of Compound (IIIc) used is preferably about 1 to about 10 times (molar ratio), more preferably about 1 to about 5 times (molar ratio) that of Compound (Iy). The base which can be employed may, for example, be an inorganic base (e.g., sodium hydride, potassium hydride, sodium hydroxide and the like), an organic base (e.g., triethylamine, pyridine, diisopropylethylamine and the like). The amount of a base, when used, is preferably about 0.5 to about 5 times (molar ratio), more preferably about 0.9 to about 2 times (molar ratio) that of Compound (Iy).
A solvent employed in the reaction of Compound (Iy) with Compound (IIIc) which does not affect the reaction adversely may, for example, be a sulfoxide (e.g., dimethyl sulfoxide and the like), an ether (e.g., diethyl ether, tetrahydrofuran, dioxane and the like), a nitrile (e.g., acetonitrile and the like), an aromatic hydrocarbon (e.g., benzene, toluene, xylene and the like), a halogenated hydrocarbon (e.g., dichloromethane, chloroform, 1,2-dichloroethane and the like), an ester (e.g., ethyl acetate), an amide (e.g., dimethylformamide, acetamide, dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidone and the like) and the like. Any of these solvent may be employed alone or in combination of two or more in an appropriate ratio.
A reaction of Compound (Iy) with Compound (IIIc) is performed at a temperature preferably of about xe2x88x9210xc2x0 C. to 150xc2x0 C., more preferably about 0xc2x0 C. to 120xc2x0 C. The reaction times ranges from about 0.5 to about 50 hours, preferably about 0.5 hours to about 30 hours.
Compound (Ib) of the invention wherein R1 is a lower (C1-4) alkyl group can be produced by reacting a compound represented by the formula: 
wherein R1b is a hydrogen atom of a lower (C1-6) alkyl group, and each of the other symbols is as defined above or a salt thereof with a compound represented by the formula:
R1cxe2x80x94OHxe2x80x83xe2x80x83(IIId)
wherein R1c is a lower (C1-6) alkyl group.
A reaction of Compound (Iz) with Compound (IIId) can be performed in the presence of an acid in a solvent which does not affect the reaction adversely or using no solvent. In this reaction, Compound (IIId) is used in excess of Compound (Iz), usually in an amount greater by about 10 to about 300 times (molar ratio). The acid which can be employed may for example be an inorganic acid (e.g., sulfuric acid, hydrochloric acid, phosphoric acid and the like) or an organic acid (e.g., toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid and the like), and the amount used is preferably about 0.001 to about 50 times (molar ratio), more preferably about 0.1 to about 5 times (molar ratio) that of Compound (Iz).
A solvent employed in the reaction of Compound (Iz) with Compound (IIId) which does not affect the reaction adversely may, for example, be a sulfoxide (e.g., dimethyl sulfoxide and the like), an ether (e.g., diethyl ether, tetrahydrofuran, dioxane and the like), a nitrile (e.g., acetonitrile and the like), an aromatic hydrocarbon (e.g., benzene, toluene, xylene and the like), a halogenated hydrocarbon (e.g., dichloromethane, chloroform, 1,2-dichloroethane and the like), an amide (e.g., dimethylformamide, acetamide, dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidone and the like) and the like. Any of these solvent may be employed alone or in combination of two or more in an appropriate ratio.
A reaction of Compound (Iz) with Compound (IIId) is performed at a temperature preferably of about 0xc2x0 C. to 150xc2x0 C., more preferably about 10xc2x0 C. to 120xc2x0 C. The reaction times range from about 1 to about 300 hours, preferably about 10 hours to about 200 hours. Compound (Ia) of the invention wherein R and R0 together form a bond and a group represented by the formula: 
wherein n is as defined above is a group represented by the formula: 
wherein n is as defined above, i.e., Compound (Ic) can, for example, be produced by subjecting a compound represented by the formula: 
wherein each symbol is as defined above or a salt thereof to a ring closure reaction. Such a ring closure reaction can usually be performed by a procedure employed for dehydrating a carboxyl group and an amino group to condense into an amido bond, such as one described in xe2x80x9cIzumiya et.al., Basics and Expeiments of Peptide Synthesis, Maruzen (1985)xe2x80x9d.
More typically, such a ring closure reaction can be performed by bringing Compound (IIb) into contact with a condensing agent in a solvent which does not affect the reaction adversely in the presence or absence of a base and in the presence and absence of an additive.
A solvent employed in this reaction which does not affect the reaction adversely may, for example, be a sulfoxide (e.g., dimethyl sulfoxide and the like), an ether (e.g., diethyl ether, tetrahydrofuran, dioxane and the like), a nitrile (e.g., acetonitrile and the like), an aromatic hydrocarbon (e.g., benzene, toluene, xylene and the like), a halogenated hydrocarbon (e.g., dichloromethane, chloroform, 1,2-dichloroethane and the like), an ester (e.g., ethyl acetate and the like), an amide (e.g., dimethylformamide, acetamide, dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidone and the like) and the like. Any of these solvent may be employed alone or in combination of two or more in an appropriate ratio.
Such a base may, for example, be an organic base (e.g., triethylamine, pyridine, diisopropylamine and the like) and the like. The amount of a base, when used, is preferably about 0.01 to about 100 times (molar ratio), more preferably about 0.1 to about 10 times (molar ratio) that of Compound (IIb).
The additive which can be employed as described above may, for example, be an active esterificating agent (e.g., 1-hydroxybenzotriazole, N-hydroxysuccinimide and the like). The amount of an additive, when used, is preferably about 0.01 to about 100 times (molar ratio), more preferably about 0.1 to about 10 times (molar ratio) that of Compound (IIb).
A condensing agent may, for example, be N,Nxe2x80x2-dicyclohexycarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, diethyl cyanophosphate, diphenylphosphorylazide and carbonyldiimidazole, with N.Nxe2x80x2-dicyclohexylcarbodiimide and diethyl cyanophosphate being preferred particularly. The amount of a condensing agent, when used, is preferably about 0.01 to about 100 times (molar ratio), more preferably about 0.1 to about 10 times (molar ratio) that of Compound (IIb). The reaction temperature is preferably about xe2x88x9210xc2x0 C. to 100xc2x0 C., more preferably about 0xc2x0 C. to 50xc2x0 C. The reaction times range from about 0.5 to about 50 hours, preferably about 0.5 hours to about 30 hours.
An inventive Compound (Iaa), (Ibb), (Icc), (Ia), (Ib) or (Ic) thus obtained can be isolated and purified by a method known per se such as extraction, condensation, neutralization, filtration, crystallization, recrystallization, chromatography and the like.
When an inventive Compound (Iaa), (Ibb), (Icc), (Ia), (Ib) or (Ic) thus obtained is a compound which is a mixture of the two compounds in each of which a group represented by the formula: 
wherein n is as defined above is a group represented by the formula: 
wherein n is as defined above and is a group represented by the formula: 
wherein n is as defined above, respectively, then the separation may be conducted by a known isomer separation method such as silica gel chromatography using ethyl acetate/water as an eluent, an octadecyl column chromatography using methanol/water/acetic acid, and the like.
Also when a product is a mixture of the two compounds in each of which a group represented by the formula: 
wherein n is as defined above is a group represented by the formula: 
wherein n is as defined above, and a group represented by the formula: 
wherein n is as defined above, respectively, then the separation may similarly be accomplished.
A prodrug for an inventive Compound (Iaa) or (Ia) is a compound which is converted into Compound (Iaa) or (Ia) under a physiological condition as a result of a reaction with an enzyme or gastric acid, thus a compound undergoing an enzymatic oxidation, reduction or hydrolyzation to form Compound (Iaa) or (Ia) and a compound hydrolyzed by gastric acid to form Compound (Iaa) or (Ia). A prodrug for Compound (Iaa) or (Ia) may, for example, be a compound obtained by subjecting an amino group in Compound (Iaa) or (Ia) to an acylation, alkylation or phosphorylation (e.g., a compound obtained by subjecting an amino group in Compound (Iaa) or (Ia) to an eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation and tert-butylation); a compound obtained by subjecting a hydroxy group in Compound (Iaa) or (Ia) to an acylation, alkylation, phosphorylation and boration (e.g., a compound obtained by subjecting a hydroxy group in Compound (Iaa) or (Ia) to an acetylation, palmitoylation, propanoylation, pivaloylation, succinylation, fumarylation, alanylation and dimethylaminomethylcarbonylation); a compound obtained by subjecting a carboxyl group in Compound (Iaa) or (Ia) to an esterification or amidation (e.g, a compound obtained by subjecting a carboxyl group in Compound (Iaa) or (Ia) to an ethylesterification, phenylesterification, carboxymethylesterification, dimethylaminomethylesterification, pivaloyloxymethylesterification, ethoxycarbonyloxyethylesterification, phthalidylesterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterification, cyclohexyloxycarbonylethylesterification and methylamidation) and the like. Any of these compounds can be produced from Compound (Iaa) or (Ia) by a method known per se.
A prodrug for Compound (Iaa) or (Ia) may also be one which is converted into Compound (Iaa) or (Ia) under a physiological condition, such as those described in xe2x80x9cIYAKUHIN no KAIHATSU (Development of Pharmaceuticals)xe2x80x9d, Vol.7, Design of Molecules, p.163-198, Published by HIROKAWA SHOTEN (1990).
Alternatively, an inventive Compound (Iaa), (Ibb), (Icc), (Ia), (Ib) or (Ic) or Compound (Ie) may, for example, be converted into a salt with an inorganic base, organic base, inorganic acid, organic acid, basic or acidic amino acid. A salt with an inorganic base may, for example, be an alkaline metal salt such as sodium and potassium salts, an alkaline earth metal salt such as calcium and magnesium salts, aluminum and ammonium salts, and a salt with an organic base may, for example, be a salt with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine or N,Nxe2x80x2-dibenzylethylenediamine. A salt with an inorganic acid may, for example, be a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid or phosphoric acid, and a salt with an organic acid may, for example, be a salt with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid. A salt with a basic amino acid may, for example, be a salt with arginine, lysine or ornithine, and a salt with acidic amino acid may, for example, be a salt with aspartic acid or glutamic acid.
Furthermore, a prodrug for an inventive Compound in (Iaa) or (Ia) may also be converted into a similar salt.
An inventive Compound (Iaa), (Ibb), (Icc), (Ia), (Ib) or (Ic) or Compound (Ie) may be a hydrate or an anhydride, and a prodrug for an inventive Compound (Iaa) or (Ia) may also be a hydrate or an anhydride.
Furthermore, an inventive Compound (Iaa), (Ibb), (Icc), (Ia), (Ib) or (Ic) or Compound (Ie) may be labeled with a radioisotope (e.g. , 3H, 14C, 35S, 225I and the like), and a prodrug for an inventive Compound (Iaa) or (Ia) may also be labeled similarly.
When an asymmetric carbon atom is present in a cycloalkene ring in an inventive Compound (Iaa), (Ibb), (Ia) or (Ib), Compound (Inn), (Icc), (In) or (Ic) can, for example, be present as any of at least two stereoisomers (optical isomers) as discribed above, which can be produced separately if necessary.
For example, a single isomer represented by the formula: 
wherein each symbol is as defined above, or by the formula: 
wherein each symbol is as defined above, or by the formula: 
wherein each symbol is as defined above, in which a group represented by the formula: 
wherein n is as defined above in a starting Compound (Ix), (Iy) or (iz) is a group represented by the formula: 
wherein n is as defined above and * represents a single steric configuration of the designated carbon atom or a single isomer of a compound represented by the formula (IIb), i.e., a compound represented by the formula: 
wherein each symbol is as defined above can be employed to perform the reaction described above to obtain a single isomer of inventive Compound (In) or (Ic).
When Compound (Inn), (Icc), (In) or (Ic) is a mixture of two or more isomers, an ordinary separation method, such as a method in which a salt with an optically active acid (e.g., camphorsulfonic acid and the like) or an optically active base (e.g., 1-methylbenzylamine and the like) is formed, various chromatographic methods (e.g., a liquid chromatography on an optically active column) and a fractional recrystalization may be employed to resolve into discrete isomers.
A compound represented by the formula (IIa), (IIIa), (Ix), (IIIb), (Iy), (IIIc), (Iz), (IIb), (Ixe2x80x2x), (Ixe2x80x2y), (Ixe2x80x2z) or (IIxe2x80x2b) can also be used as a salt, and such salt of each of these compounds may be any of the salts which do not affect the reaction adversely, such as a salt with an inorganic base, organic base, inorganic acid, organic acid, basic or acidic amino acid. A salt with an inorganic base may, for example, be an alkaline metal salt such as sodium and potassium salts, an alkaline earth metal salt such as calcium and magnesium salts, aluminum and ammonium salts, and a salt with an organic base may, for example, be a salt with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine or N,Nxe2x80x2-dibenzylethylenediamine. A salt with an inorganic acid may, for example, be a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid or phosphoric acid, and a salt with an organic salt may, for example, be a salt with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid. A salt with a basic amino acid may, for example, be a salt with arginine, lysine or ornithine, and a salt with acidic amino acid may, for example, be a salt with aspartic acid or glutamic acid.
Compound (IIe) which is a starting compound (IIa) in the invention wherein R1 is ethyl and X1 is a chlorine atom may, for example, be produced by a method represented by the following scheme. 
A method for producing a starting Compound (IIc) in this scheme is known per se, and may, for example, be in accordance with the description in Tetrahedron, Vol.28,p.5923 (1972) and Vol.30, p.3753 (1974) or analogous methods.
A method for producing a compound (IIa) wherein R1 is ethyl, X1 is a chlorine atom and wherein n is 1 represented by the formula: 
and wherein n is 2 represented by the formula: 
is known per se, and may, for example, be in accordance with the description in Journal of the American Chemical Society, Vol.101, p.6981 (1979) or analogous methods.
A method for producing a compound (IIa) wherein R1 is methyl, X1 is a chlorine atom and n is 2 represented by the formula: 
is known per se, and may, for example, be in accordance with the description in Bioorganic and Medicinal Chemistry Letters, Vol.5, p.325 (1995) or analogous methods.
In order to produce other compounds encompassed in a starting Compound (IIa), a method described above or analogous methods can be employed.
A starting Compound (IIb) or (Iy) in the invention can, for example, be produced by a method represented by the following schemes. 
wherein each symbol is as defined above, and 
wherein each symbol is as defined above.
A method for producing Compound (Iy) wherein M is a hydrogen atom, R2 is a methyl group, Ar is a phenyl group, n is 2 and a group represented by the formula: 
is a group represented by the formula: 
which is a compound represented by the formula: 
is known per se, and may be in accordance with the description in Journal of the American Chemical Society, Vol.101, p.6981 (1979) or analogous methods.
A starting compound or an intermediate obtained as described above can be isolated and purified from a reaction mixture by a method known per se, such as extraction, concentration, neutralization, filtration, crystallization, recrystallization, column chromatography, thin layer chromatography and the like. It may also be used directly in the next step without any isolation.
When a resultant starting material or an intermediate is a mixture of the two compounds in each of which a group represented by the formula: 
wherein n is as defined above is a group represented by the formula: 
wherein n is as defined above and is a group represented by the formula: 
wherein n is as defined above, respectively, then the separation may be conducted by a known isomer separation method such as silica gel chromatography using ethyl acetate/water as an eluent, an octadecyl column chromatography using methanol/water/acetic acid as an eluent, and the like.
Also when a product is a mixture of the two compounds in each of which a group represented by the formula: 
wherein n is as defined above is a group represented by the formula: 
wherein n is as defined above and is a group represented by the formula: 
wherein n is as defined above, respectively, then the separation may similarly be accomplished.
Since an inventive Compound (Iaa) or Compound (Ie) has a low toxicity, an nitric oxide (NO) production-inhibiting effect and an inhibitory effect on the production of an inflammatory cytokine such as TNF-xcex1, IL-1 and IL-6, it is useful as a therapeutic and/or prophylactic agent in a mammal (e.g., cat, cattle, dog, horse, goat, monkey, human and the like) against heart disease, autoimmune disease, inflammatory disease, central nervous system disease, infectious disease, sepsis, septic shock including ichorrhemia, endotoxin shock, exotoxin shock, cardiac deficiency, shock, hypotension, rheumatoid arthritis, osteoarthritis, gastritis, ulcerative colitis, peptic ulcer, stress-induced gastric ulcer, Crohn""s disease, autoimmune disease, post-transplant tissue failure and rejection, postischemic re-perfusion failure, acute coronary microvascular embolism, shock-induced vascular embolism (disseminated intravascular coagulation (DIC) and the like), ischemic cerebral disorder, arterial sclerosis, malignant anemia, Fanconi""s anemia, drepanocythemia, pancreatitis, nephrose syndrome, nephritis, renal failure insulin-dependent diabetes, insulin-independent diabetes, hepatic porphyria, alcoholism, Parkinson""s disease, chronic leukemia, acute leukemia, tumor, myeloma, side effects of anticancer agents, infantile and adult respiratory distress syndrome, pulmonary emphysema, dementia, Alzheimer""s disease, multiple sclerosis, vitamin E deficiency, aging, sunburn, muscular dystrophy, myocarditis, cardiomyopathy, myocardial infarction, sequela of myocardial infaction, osteoporosis, pneumonia, hepatitis, psoriasis, pain, cataract, influenza infection, malaria, human immunodeficiency virus (HIV) infection, radiation-induced failure, burn, in vitro fertilization efficiency, hypercalcemia, tonic spondylitis, osteopenia, bone Behcet""s disease, osteomalacia, fracture, acute bacterial meningitis, Helicobactor pylori infection, invasive staphylococcal infection, tuberculosis, systemic mycosis, herpes simplex virus infection, varicella-helpes zoster virus infection, human papilloma virus infection, acute viral encephalitis, encephalitis, asthma, atopic dermatitis, allergic rhinitis, reflux esophargitis, fever, hyper cholesteremia, hyperglycemia, hyperlipidemia, diabetic complication, diabetic renal disease, diabetic neuropathy, diabetic retinopathy, gout, gastric atony, hemorrhoid, systemic lupus erythematosus, spinal damage, insomnia, schizophrenia, epilepsy, cirrhosis, hepatic failure, instable angina, valvular disease, dialysis-induced thrombocytopenia, acute ischemic cerebral apoplexy, acute cerebral thrombosis, cancer metastasis, urinary bladder cancer, mammary cancer, uterine cervical cancer, colon cancer, gastric cancer, ovarian cancer, prostatic cancer, parvicellular pulmonary cancer, non-parvicellular pulmonary cancer, malignant melanoma, Hodgkin""s disease, non-Hodgkin lymphoma and the like.
When an inventive Compound (Iaa) or Compound (Ie) is administered to a human, it is given safely as it is or in a mixture with an appropriate pharmacologically acceptable carrier, excipient and diluent, in a dosage form such as an oral formulation (e.g., powder, granlue, tablet, capsule and the like), a parenteral formulation (e.g., injection formulation, dermal formulation (e.g., nasal formulation, percutaneous formulation and the like), suppository (e.g., rectal suppository and vaginal suppository and the like) as well as other oral or parenteral pharmaceutical composition.
Any of these formulations may be produced by any method known per se which is employed ordinarily for producing a pharmaceutical formulation. The amount of an inventive Compound (Iaa) or Compound (Ie) to be incorporated into a formulation may vary depending on the dosage forms, and is preferably about 10 to 95% by weight in an oral formulation described above and about 0.001 to about 95% by weight in a parenteral formulation described above.
For example, an injection formulation can be produced by formulating an inventive Compound (Iaa) or Compound (Ie) together with a solubilizing agent (e.g., xcex2-cyclodextrin and the like), a dispersant (e.g.,, Tween 80 (ATLASPOWDER USA), HCO60 (NIKKO CHEMICALS), carboxymethyl cellulose, sodium alginate and the like), a preservative (e.g., methylparaben, propylparaben, benzyl alcohol, chlorobutanol and the like), an isotonic agent (e.g., sodium chloride, glycerin, sorbitol, glucose and the like) into an aqueous injection formulation in accordance with an ordinary method, or by suspending or emulsifying an active ingredient in a vegetable oil (e.g., olive oil, sesame oil, peanut oil, cottonseed oil, corn oil and the like) and propylene glycol to form an oil-based injection formulation.
An oral formulation can be produced by compressing an inventive Compound (Iaa) or Compound (Ie) together with an excipient (e.g., lactose, sucrose, starch and the like), a disintegrant (e.g., starch, calcium carbonate and the like), a binder (e.g., starch, gum arabic, carboxymethyl cellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose and the like) or a glidant (e.g., talc, magnesium stearate, polyethylene glycol 6000 and the like) as appropriate followed by a coating process known per se for the purpose of masking a taste, forming an enteric coat, or achieving a sustained release. Such coating may, for example, be hydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, Eudragit (ROHME, Germany, a copolymer of methacrylic acid and acrylic acid), a dye (e.g., titanium oxide, iron oxide red and the like) as appropriate.
An inventive Compound (Iaa) or Compound (Ie) can also be employed as a dermal formulation in the form of a solid or semi-solid or a liquid.
For example, a solid dermal formulation may be an inventive Compound (Iaa) or Compound (Ie) as it is or in a mixture with an excipient (e.g., glycol, mannitol, starch, microcrystalline cellulose and the like), a thickening agent (e.g., natural gums, cellulose derivatives, acrylic acid polymers and the like) which is then converted into a powder composition. A semi-solid dermal formulation may be produced by a standard method in the form of an aqueous or oil-based gel or ointment. A liquid dermal formulation may be produced by a method employed for producing an injection formulation or an analogous method in the form of an oil-based or aqueous suspension.
A solid, semi-solid or liquid dermal formulation may be supplemented also with a pH modifier (e.g., carbonated water, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide and the like), an antiseptic (e.g., p-oxybenzoates, chlorobutanol, benzalkonium chloride and the like) and the like, as appropriate. Typically, a vaseline or a lanolin is used as a formulation base, per 1 g of which about 0.1 to 100 mg of an inventive Compound (Iaa) or Compound (Ie) is contained to form an ointment.
An inventive Compound (Iaa) or Compound (Ie) may be formulated also as an oil-based or aqueous solid or semi-solid or liquid suppository. An oil-based suppository base may, for example, be a higher fatty glyceride (e.g., cocoa butter, WITEPSOL (DYNAMIT NOBEL) and the like), a middle fatty acid (e.g., MYGLYOL (DYNAMIT NOBEL) and the like), or a vegetable oil (e.g., sesame oil, soybean oil, cottonseed oil and the like) and the like as appropriate. An aqueous base may, for example, be a polyethylene glycols or a propylene glycol, and an aqueous gel base may, for example, be a natural gum, a cellulose derivative, a vinyl polymer, an acrylic polymer and the like.
While the dose of an inventive Compound (Iaa) or Compound (Ie) may vary depending on the patient""s age, body weight and condition, the dosage form, the mode and the period of the treatment, it may, for example, be generally about 0.01 to about 1000 mg/kg, preferably about 0.01 to about 100 mg/kg, more preferably about 0.1 to about 100 mg/kg, most preferably about 0.1 to about 50 mg/kg, and particularly about 1.5 to about 30 mg/kg per day in a patient having a sepsis (adult weighing about 60 kg), said daily dose being given orally or parenterally all at once or in portions during a day. It is a matter of course that a lower daily dose may be sufficient or an excessive dose may be required since the dose may vary depending on various factors as discussed above.
The present invention is further described with referring to Reference Examples, Examples, Preparation Examples and Experiments, which are not intended to restrict the invention.
A 1H NMR spectrum was determined by a VARIAN GEMINI 200 (200 MHz) spectrometer using tetramethyl silane as an internal standard and represented as the entire xcex4 values in ppm. The number in a bracket when a solvent mixture was employed is the volume ratio of each mixture. A % is a % by weight unless otherwise specified. The ratio of the solvents in a chromatography on silica gel is the volume ratio of the solvents to be admixed.
A more polar diastereomer means a diastereomer having a smaller Rf value when determined by a normal phase thin layer chromatography under a same condition (for example using ethyl acetate/hexane as an eluent), which a less polar diastereomer means a diastereomer having a larger Rf value in such determination.
The meanings of the abbreviations as used in the
Examples are as follows:
s: singlet d: doublet: t: triplet q: quartet DD: double doublet tt: triple triplet m: multiplet br: broad J: coupling constant